PROJECT SUMMARY Chronic kidney disease (CKD) is usually considered to be an irreversible process that often results in end stage renal failure (ESRF), a devastating disorder whose incidence has grown approximately 20-25% during the past decade and accounts about 10% of the total population in the United States. It is unlikely that this high morbidity and associated financial burden will be reduced until we have a better understanding of the molecular and cellular pathogenesis of CKD and develop effective and specific treatment. Interstitial fibrosis, one of the hallmarks of CKD, is generally considered to be the determinant prognosis factor of CKD. In previous in vitro studies, we discovered that p90 ribosomal S6 kinase (p90RSK) promotes LDL receptor- related protein-1 (LRP-1)-mediated interstitial fibroblast proliferation and survival, leading to renal interstitial fibrosis and the progression of CKD. However, the roles of p90RSK and LRP-1 in renal fibrogenesis in vivo have never been investigated. Our central hypothesis is that, in response to chronic kidney injury, the LRP-1 and p90RSK signaling cascade is activated, which promotes renal fibrosis and CKD progression; and that pharmacological inhibition of p90RSK alleviates kidney damage and fibrosis. This hypothesis will be tested by addressing the following specific aims using both in vitro and in vivo approaches: Specific Aim 1 will determine the role of p90RSK in CKD in the novel inducible fibroblast-specific p90RSK transgenic mice. Specific Aim 2 will determine the role of LRP-1 in CKD in the unique fibroblast-specific LRP-1 knockout mice. Specific Aim 3 will determine the therapeutic efficacy of p90RSK inhibition for CKD treatment. The proposed investigations will illuminate novel functions of p90RSK and LRP-1 in renal fibrosis and provide innovative insights into the mechanisms underlying renal fibrogenesis. These studies have translational significance that they will test the therapeutic efficacy of inhibition of p90RSK signaling in the treatment of CKD and will stimulate the development of novel clinical interventions designed to halt or reverse the progression of CKD.